|Ph.D Student||Razon Hila|
|Subject||The Role of Chemokine and their Receptors in Shaping|
the Tumor Microenvironment
|Department||Department of Medicine||Supervisor||Professor Nathan Karin|
|Full Thesis text|
The tumor microenvironment (TME) consists of stromal cells, immune cells, bone marrow-derived cells (BM-derived cells), the extracellular matrix and various secreted soluble factors, including cytokines, such as chemokines, and growth factors.
Chemokines are small, structurally related cytokines that regulate cell trafficking via interactions with G protein-coupled receptors. An array of chemokine receptors is expressed on cells in the TME, including tumor and immune cells.
My thesis focused on exploring the role of chemokines and their receptors in shaping the TME either by supporting cancer development and spread or by promoting its elimination via enhancement of the anti-tumor immune response.
Tumor-infiltrating leukocytes play a dual role in cancer. They suppress tumor growth by destroying cancer cells or inhibiting their outgrowth, but they also promote tumor progression by inducing immune suppression. Among the cells that suppress anti-tumor immunity are regulatory T cells, tumor-associated macrophages and myeloid derived suppressor cells (MDSCs). MDSC comprise CD11b???? polymorphonuclear myeloid cells (PMN-MDSC), and CD11b???? monocytic myeloid cells (Mo-MDSC). These BM-derived cells are mobilized from BM to blood and then colonize tumor sites where they promote the development and progression of tumors. The CCR2-CCL2 axis has been identified as the key driver of the recruitment of monocytic cells to the TME.
The first part of my thesis focused on the mechanism by which PMN-MDSC are mobilized from the bone marrow to the blood in two different models of cancer; The TRAMP-C1 prostate cancer autologous transferred model and RET melanoma autologous transferred model. The findings in these models were complementary, clearly showing that the interaction of CCR5 on BM-derived cells and its ligands, largely secreted by the tumor, direct the mobilization of PMN-MDSCs from BM to blood to accumulate in the TME. I showed that CCR5 and its ligands are associated with selective colonization of these cells at the tumor site. The underlying mechanism is still needs to be explored. I also demonstrated that the interaction of CCR5 and its ligands directs the suppressive activities of PMN-MDSCs at the tumor site, partly by increasing arginase-1.
The second part of my study focused on CXCL10 that has been implicated with the potentiation of effector CD4 T cells. Here we used a stabilized form of CXCL10
(CXCL10-Ig) to suppress melanoma and clearly showed that this is associated with induction of CD8 T cell immunity against the tumor. My thesis shows that CXCL10 induces CD8 T cell activation and proliferation in the periphery, mediates migration of cytotoxic T lymphocytes to the TME and facilitates their specific anti-tumor response, which restrains tumor development. Adoptive transfer experiments are still required to study whether CXCL10 directly potentiates CD8 T cells or via its effect on CD4 effector T cells.
Collectively both studies implicate for a key role of chemokines and their receptors in shaping tumor microenvironment and suggest novel ways of therapy.